A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis

Manikuntala Kundu, Sushil Kumar Pathak, Kuldeep Kumawat, Sanchita Basu, Gargi Chatterjee, Shresh Pathak, Takuya Noguchi, Kohsuke Takeda, Hidenori Ichijo, Christine B.F. Thien, Wallace Y. Langdon, Joyoti Basu

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54 Citations (Scopus)

Abstract

Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.

Original languageEnglish
Pages (from-to)918-926
Number of pages9
JournalNature Immunology
Volume10
Issue number8
DOIs
Publication statusPublished - 2009 Jul 14
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kundu, M., Pathak, S. K., Kumawat, K., Basu, S., Chatterjee, G., Pathak, S., Noguchi, T., Takeda, K., Ichijo, H., Thien, C. B. F., Langdon, W. Y., & Basu, J. (2009). A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis. Nature Immunology, 10(8), 918-926. https://doi.org/10.1038/ni.1754